tbuckley/cabot-search huggingface dataset:
Direct identification of HLA class I and class II-restricted T cell epitopes in pancreatic cancer tissues by mass spectrometry
Authors: Kenji Fujiwara, Yingkuan Shao, Nan Niu, Tengyi Zhang, Brian Herbst, Mackenzie Henderson, Stephen Muth, Pingbo Zhang, Lei Zheng
Journal: Journal of Hematology & Oncology (2022)

Identifying T cell epitopes on pancreatic ductal adenocarcinoma (PDAC) associated antigens or neoantigens has been a challenge. In this study, we attempted to identify PDAC T cell epitopes by mass spectrometry (MS). We isolated HLA class I (HLA-I) and HLA class II (HLA-II)-restricted peptides, respectively, from tissues of human PDAC by using the pan-HLA-I or pan-HLA-II affinity purification column and identified T cell epitopes by peptidome analysis with MS. Through peptidome analysis, we identified T cell epitopes shared by multiple patients with different HLA types and those containing sequences of both anti-HLA-I and HLA-II antibodies-affinity purified peptides. The identified epitopes bound non-matched HLA molecules and induced T cell response in peripheral T cells from both HLA-type matched and non-matched patients. Peptides containing both HLA class I and class II epitopes were able to induce polyfunctional cytokine responses in peripheral T cells. T cell epitopes in PDAC can be discovered by the MS approach and can be designed into vaccine and TCR-T cell therapies for both HLA-type matched and non-matched patients.
UNcommon EGFR Mutations: International Case Series on Efficacy of Osimertinib in Real-Life Practice in First-LiNe Setting (UNICORN)
Authors: Jair Bar, Nir Peled, Shiruyeh Schokrpur, Mirjana Wolner, Ofer Rotem, Nicolas Girard, Frank Aboubakar Nana, Sofie Derijcke, Waleed Kian, Sandip Patel, Hadas Gantz-Sorotsky, Alona Zer, Mor Moskovitz, Giulio Metro, Yakir Rottenberg, Antonio Calles, Maximilian Hochmair, Kristof Cuppens, Lynn Decoster, Martin Reck, Dror Limon, Estelamari Rodriguez, Christoforos Astaras, Adrienne Bettini, Simon Häfliger, Alfredo Addeo
Journal: Journal of Thoracic Oncology (2022)

IntroductionApproximately 10% of EGFR mutations (EGFRmuts) are uncommon (ucEGFRmuts). We aimed to collect real-world data about osimertinib for patients with ucEGFRmuts.MethodsThis is a multicenter, retrospective study of ucEGFRmut (exon 20 insertions excluded) metastatic NSCLC treated with osimertinib as first EGFR inhibitor. The Response Evaluation Criteria in Solid Tumors and response assessment in neuro-oncology brain metastases brain objective response rate (ORR) were evaluated by the investigators. Median progression-free survival (mPFS), median overall survival, and median duration of response (mDOR) were calculated from osimertinib initiation. Mutations found at resistance were collected.ResultsA total of 60 patients were included (22 centers, nine countries), with median age of 64 years, 75% females, and 83% Caucasian. The largest subgroups were G719X (30%), L861Q (20%), and de novo Thr790Met (T790M) (15%). The ORR was 61%, mPFS 9.5 months, mDOR 17.4 months, and median overall survival 24.5 months. Regarding patients with no concurrent common mutations or T790M (group A, n = 44), ORR was 60%, mPFS 8.6 months, and mDOR 11 months. For G719X, ORR was 47%, mPFS 8.8 months, and mDOR 9.1 months. For L861Q, ORR was 80%, mPFS 16 months, and mDOR 16 months. For de novo T790M, ORR was 44%, mPFS 12.7 months, and mDOR 46.2 months. Compound EGFRmut including common mutations had better outcome compared with only ucEGFRmut. For 13 patients with a response assessment in neuro-oncology brain metastases–evaluable brain metastases, brain ORR was 46%. For 14 patients, rebiopsy results were analyzed: four patients with additional EGFR mutation (C797S, D585Y, E709K), three with new TP53 mutation, one with c-Met amplification, one with PIK3CA mutation, and one with neuroendocrine transformation.ConclusionsOsimertinib was found to have an activity in ucEGFRmut with a high rate of disease control systemically and intracranially. Several resistance mechanisms were identified. This report comprises, to the best of our knowledge, the largest data set of its kind.
Myelin repair in Alzheimer’s disease: a review of biological pathways and potential therapeutics
Authors: Lauren Rose Hirschfeld, Shannon L. Risacher, Kwangsik Nho, Andrew J. Saykin
Journal: Translational Neurodegeneration (2022)

Abstract This literature review investigates the significant overlap between myelin-repair signaling pathways and pathways known to contribute to hallmark pathologies of Alzheimer’s disease (AD). We discuss previously investigated therapeutic targets of amyloid, tau, and ApoE, as well as other potential therapeutic targets that have been empirically shown to contribute to both remyelination and progression of AD. Current evidence shows that there are multiple AD-relevant pathways which overlap significantly with remyelination and myelin repair through the encouragement of oligodendrocyte proliferation, maturation, and myelin production. There is a present need for a single, cohesive model of myelin homeostasis in AD. While determining a causative pathway is beyond the scope of this review, it may be possible to investigate the pathological overlap of myelin repair and AD through therapeutic approaches.
Obesity alone should not rule out knee replacement surgery
Authors: Helen Saul, Deniz Gursul, Jonathan Evans
Journal: BMJ (2022)

The studyEvans JT, Mouchti S, Blom AW, et al. Obesity and revision surgery, mortality, and patient-reported outcomes after primary knee replacement surgery in the National Joint Registry: a UK cohort study. PLoS Med 2021;18:7.
Significant variation in the performance of DNA methylation predictors across data preprocessing and normalization strategies
Authors: Anil P. S. Ori, Ake T. Lu, Steve Horvath, Roel A. Ophoff
Journal: Genome biology (2022)

DNA methylation (DNAm)-based predictors hold great promise to serve as clinical tools for health interventions and disease management. While these algorithms often have high prediction accuracy, the consistency of their performance remains to be determined. We therefore conduct a systematic evaluation across 101 different DNAm data preprocessing and normalization strategies and assess how each analytical strategy affects the consistency of 41 DNAm-based predictors.
Making better use of natural experimental evaluation in population health
Authors: Peter Craig, Mhairi Campbell, Adrian Bauman, Manuela Deidda, Ruth Dundas, Niamh Fitzgerald, Judith Green, Srinivasa Vittal Katikireddi, Jim Lewsey, David Ogilvie, Frank de Vocht, Martin White
Journal: BMJ (2022)

Rather than arguing about the suitability of natural experimental methods to inform decisions we need to focus on refining their scope and design, say Peter Craig and colleagues Key messages• Natural experimental evaluations can provide useful information to guide decision making about interventions• Most discussion has focussed on what quantitative methods are suitable for natural experimental evaluations Key definitions and concepts remain contested and there is a lack of consensus about the circumstances in which natural experimental evaluations can provide trustworthy and useful evidence for decision-making• Guidance should help identify the circumstances that make for good natural experimental evaluation, and a range of applicable methods
Improved Protocols for Ventilator Liberation
Authors: C. Corey Hardin
Journal: New England Journal of Medicine (2022)

Like many critical care interventions, mechanical ventilation is lifesaving when indicated but is beset by potential complications as the duration of use increases. Early identification of patients who are ready to be liberated from ventilator support is therefore key to the management of respiratory failure. Because clinician judgment lacks both sensitivity and specificity for identifying such patients,1 this task is best accomplished by means of protocolized spontaneous-breathing trials,2,3 in which patients who meet a defined set of criteria undergo a test period of minimal or no ventilator support. Many, if not most, patients who meet the criteria for a spontaneous-breathing . . .
Mental Health Outcomes Following Extracorporeal Membrane Oxygenation in Survivors of Critical Illness
Authors: Marieke Zegers, Mark van den Boogaard, J. G. (Hans) van der Hoeven
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Association Between Selective Decontamination of the Digestive Tract and In-Hospital Mortality in Intensive Care Unit Patients Receiving Mechanical Ventilation
Authors: Naomi E. Hammond, John Myburgh, Ian Seppelt, Tessa Garside, Ruan Vlok, Sajeev Mahendran, Derick Adigbli, Simon Finfer, Ya Gao, Fiona Goodman, Gordon Guyatt, Joseph Alvin Santos, Balasubramanian Venkatesh, Liang Yao, Gian Luca Di Tanna, Anthony Delaney
Journal: JAMA (2022)

Importance The effectiveness of selective decontamination of the digestive tract (SDD) in critically ill adults receiving mechanical ventilation is uncertain. Objective To determine whether SDD is associated with reduced risk of death in adults receiving mechanical ventilation in intensive care units (ICUs) compared with standard care. Data Sources The primary search was conducted using MEDLINE, EMBASE, and CENTRAL databases until September 2022. Study Selection Randomized clinical trials including adults receiving mechanical ventilation in the ICU comparing SDD vs standard care or placebo. Data Extraction and Synthesis Data extraction and risk of bias assessments were performed in duplicate. The primary analysis was conducted using a bayesian framework. Main Outcomes and Measures The primary outcome was hospital mortality. Subgroups included SDD with an intravenous agent compared with SDD without an intravenous agent. There were 8 secondary outcomes including the incidence of ventilator-associated pneumonia, ICU-acquired bacteremia, and the incidence of positive cultures of antimicrobial-resistant organisms. Results There were 32 randomized clinical trials including 24 389 participants in the analysis. The median age of participants in the included studies was 54 years (IQR, 44-60), and the median proportion of female trial participants was 33% (IQR, 25%-38%). Data from 30 trials including 24 034 participants contributed to the primary outcome. The pooled estimated risk ratio (RR) for mortality for SDD compared with standard care was 0.91 (95% credible interval [CrI], 0.82-0.99; I 2 = 33.9%; moderate certainty) with a 99.3% posterior probability that SDD reduced hospital mortality. The beneficial association of SDD was evident in trials with an intravenous agent (RR, 0.84 [95% CrI, 0.74-0.94]), but not in trials without an intravenous agent (RR, 1.01 [95% CrI, 0.91-1.11]) ( P value for the interaction between subgroups = .02). SDD was associated with reduced risk of ventilator-associated pneumonia (RR, 0.44 [95% CrI, 0.36-0.54]) and ICU-acquired bacteremia (RR, 0.68 [95% CrI, 0.57-0.81]). Available data regarding the incidence of positive cultures of antimicrobial-resistant organisms were not amenable to pooling and were of very low certainty. Conclusions and Relevance Among adults in the ICU treated with mechanical ventilation, the use of SDD compared with standard care or placebo was associated with lower hospital mortality. Evidence regarding the effect of SDD on antimicrobial resistance was of very low certainty.
Early Oxygen Supplementation After Resuscitation From Cardiac Arrest
Authors: Jonathan Elmer, Francis X. Guyette
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Spontaneous-Breathing Trials with Pressure-Support Ventilation or a T-Piece
Authors: Arnaud W Thille, Arnaud Gacouin, Rémi Coudroy, Stephan Ehrmann, Jean-Pierre Quenot, Mai-Anh Nay, Christophe Guitton, Damien Contou, Guylaine Labro, Jean Reignier, Gael Pradel, Gaëtan Beduneau, Laurence Dangers, Clement Saccheri, Gwénaël Prat, Guillaume Lacave, Nicholas Sedillot, Nicolas Terzi, Béatrice La Combe, Jean-Paul Mira, Antoine Romen, Marie-Ange Azais, Anahita Rouzé, Jérôme Devaquet, Agathe Delbove, Martin Dres, Jeremy Bourenne, Alexandre Lautrette, Joe de Keizer, Stéphanie Ragot, Jean-Pierre Frat
Journal: New England Journal of Medicine (2022)

Spontaneous-breathing trials can be performed with the use of either pressure-support ventilation (PSV) or a T-piece. Whether PSV trials may result in a shorter time to tracheal extubation than T-piece trials, without resulting in a higher risk of reintubation, among patients who have a high risk of extubation failure is unknown.In this multicenter, open-label trial, we randomly assigned patients who had a high risk of extubation failure (i.e., were &gt;65 years of age or had an underlying chronic cardiac or respiratory disease) to undergo spontaneous-breathing trials performed with the use of either PSV (with a pressure-support level of 8 cm of water and no positive end-expiratory pressure) or a T-piece. The primary outcome was the total time without exposure to invasive ventilation (reported as the number of ventilator-free days) at day 28 after the initial spontaneous-breathing trial. Secondary outcomes included extubation within 24 hours and extubation within 7 days after the initial spontaneous-breathing trial, as well as reintubation within 7 days after extubation.A total of 969 patients (484 in the PSV group and 485 in the T-piece group) were included in the analysis. At day 28, the median number of ventilator-free days was 27 (interquartile range, 24 to 27) in the PSV group and 27 (interquartile range, 23 to 27) in the T-piece group (difference, 0 days; 95% confidence interval [CI], -0.5 to 1; P = 0.31). Extubation was performed within 24 hours in 376 patients (77.7%) in the PSV group and in 350 patients (72.2%) in the T-piece group (difference, 5.5 percentage points; 95% CI, 0.01 to 10.9), and extubation was performed within 7 days in 473 patients (97.7%) and 458 patients (94.4%), respectively (difference, 3.3 percentage points; 95% CI, 0.8 to 5.9). Reintubation was performed in 72 of 481 patients (14.9%) in the PSV group and in 65 of 477 patients (13.6%) in the T-piece group (difference, 1.3 percentage points; 95% CI, -3.1 to 5.8). Cardiac or respiratory arrest was a reason for reintubation in 9 patients (3 in the PSV group and 6 in the T-piece group).Among patients who had a high risk of extubation failure, spontaneous-breathing trials performed with PSV did not result in significantly more ventilator-free days at day 28 than spontaneous-breathing trials performed with a T-piece. (Supported by the French Ministry of Health; TIP-EX ClinicalTrials.gov number, NCT04227639.).
Long-Term Mortality Follow-Up of Radial Artery Versus Saphenous Vein in Coronary Artery Bypass Grafting: A Multicenter, Randomized Trial
Authors: Steven Goldman, Madeline McCarren, Gulshan K. Sethi, William Holman, Faisal G. Bakaeen, Todd H. Wagner, Yajie Wang, Mei-Chung Shih, Robert Edson
Journal: Circulation (2022)
Reduce unnecessary use of proton pump inhibitors
Authors: Barbara Farrell, Elliot Lass, Paul Moayyedi, Deanna Ward, Wade Thompson
Journal: BMJ (2022)

### What you need to know Proton pump inhibitors (PPIs) are one of the most widely used classes of drugs globally, often taken for longer than needed and at high financial cost to society. Among adults living in the community, the point prevalence of PPI use is 7-8% in the UK and Denmark,12 while rates of use of 40-50% have been reported in older people in Canada and in those living in residential care in Australia.3456 In England, more than 50 million prescriptions for PPIs were issued in 2015.7 While PPIs are effective for upper gastrointestinal disorders and may be continued long term (beyond 8 weeks)8 for specific conditions (box 1),11121314 people often continue taking them for years when guidelines recommend 4-8 weeks of treatment or, in the case of gastrointestinal bleeding prophylaxis for critically ill patients, cessation when the patient is no longer critically ill or the risk factor triggering prophylaxis is no longer present (box 2).9131516 Box 1 ### Indications for long term use (>8 weeks) of proton pump inhibitors (PPIs)910RETURN TO TEXT
Nucleocapsid-specific antibody function is associated with therapeutic benefits from COVID-19 convalescent plasma therapy
Authors: Jonathan D. Herman, Chuangqi Wang, John Stephen Burke, Yonatan Zur, Hacheming Compere, Jaewon Kang, Ryan Macvicar, Sabian Taylor, Sally Shin, Ian Frank, Don Siegel, Pablo Tebas, Grace H. Choi, Pamela A. Shaw, Hyunah Yoon, Liise-anne Pirofski, Boris D. Julg, Katharine J. Bar, Douglas Lauffenburger, Galit Alter
Journal: Cell Reports Medicine (2022)

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP), a passive polyclonal antibody therapeutic agent, has had mixed clinical results. Although antibody neutralization is the predominant approach to benchmarking CCP efficacy, CCP may also influence the evolution of the endogenous antibody response. Using systems serology to comprehensively profile severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) functional antibodies of hospitalized people with COVID-19 enrolled in a randomized controlled trial of CCP (ClinicalTrials.gov: NCT04397757), we find that the clinical benefits of CCP are associated with a shift toward reduced inflammatory Spike (S) responses and enhanced nucleocapsid (N) humoral responses. We find that CCP has the greatest clinical benefit in participants with low pre-existing anti-SARS-CoV-2 antibody function and that CCP-induced immunomodulatory Fc glycan profiles and N immunodominant profiles persist for at least 2 months. We highlight a potential mechanism of action of CCP associated with durable immunomodulation, outline optimal patient characteristics for CCP treatment, and provide guidance for development of a different class of COVID-19 hyperinflammation-targeting antibody therapeutic agents.
The tie that binds: temporal coding and adaptive emotion
Authors: Jingyi Wang, Arielle Tambini, Regina C. Lapate
Journal: Trends in Cognitive Sciences (2022)

Emotions are temporally dynamic, but the persistence of emotions outside of their appropriate temporal context is detrimental to health and well-being. Yet, precisely how temporal coding and emotional processing interact remains unclear. Recently unveiled temporal context representations in the hippocampus, entorhinal cortex (EC), and prefrontal cortex (PFC) support memory for what happened when. Here, we discuss how these neural temporal representations may interact with densely interconnected amygdala circuitry to shape emotional functioning. We propose a neuroanatomically informed framework suggesting that high-fidelity temporal representations linked to dynamic experiences promote emotion regulation and adaptive emotional memories. Then, we discuss how newly-identified synaptic and molecular features of amygdala-hippocampal projections suggest that intense, amygdala-dependent emotional responses may distort temporal-coding mechanisms. We conclude by identifying key avenues for future research.
Learning shapes cortical dynamics to enhance integration of relevant sensory input
Authors: Angus Chadwick, Adil G. Khan, Jasper Poort, Antonin Blot, Sonja B. Hofer, Thomas D. Mrsic-Flogel, Maneesh Sahani
Journal: Neuron (2022)

Adaptive sensory behavior is thought to depend on processing in recurrent cortical circuits, but how dynamics in these circuits shapes the integration and transmission of sensory information is not well understood. Here, we study neural coding in recurrently connected networks of neurons driven by sensory input. We show analytically how information available in the network output varies with the alignment between feedforward input and the integrating modes of the circuit dynamics. In light of this theory, we analyzed neural population activity in the visual cortex of mice that learned to discriminate visual features. We found that over learning, slow patterns of network dynamics realigned to better integrate input relevant to the discrimination task. This realignment of network dynamics could be explained by changes in excitatory-inhibitory connectivity among neurons tuned to relevant features. These results suggest that learning tunes the temporal dynamics of cortical circuits to optimally integrate relevant sensory input.
Haloperidol for the Treatment of Delirium in ICU Patients
Authors: Nina C. Andersen-Ranberg, Lone M. Poulsen, Anders Perner, Jørn Wetterslev, Stine Estrup, Johanna Hästbacka, Matt Morgan, Giuseppe Citerio, Jesus Caballero, Theis Lange, Maj-Brit N. Kjær, Bjørn H. Ebdrup, Janus Engstrøm, Markus H. Olsen, Marie Oxenbøll Collet, Camilla B. Mortensen, Sven-Olaf Weber, A. Sofie Andreasen, Morten H. Bestle, Bülent Uslu, Helle Scharling Pedersen, Louise Gramstrup Nielsen, Hans C. Toft Boesen, Jacob V. Jensen, Lars Nebrich, Kirstine La Cour, Jens Laigaard, Cecilie Haurum, Marie W. Olesen, Christian Overgaard-Steensen, Bo Westergaard, Björn Brand, Gitte Kingo Vesterlund, Pernille Thornberg Kyhnauv, Vibe S. Mikkelsen, Simon Hyttel-Sørensen, Inge de Haas, Søren R. Aagaard, Line O. Nielsen, Anne S. Eriksen, Bodil S. Rasmussen, Helene Brix, Thomas Hildebrandt, Martin Schønemann-Lund, Hans Fjeldsøe-Nielsen, Anna-Maria Kuivalainen, Ole Mathiesen
Journal: New England Journal of Medicine (2022)

Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited.